title: Human cholangiocarcinoma development is associated with dysregulation of opioidergic modulation of cholangiocyte growth.
abstract: OBJECTIVE
  Incidence of cholangiocarcinoma is increasing worldwide, yet remaining highly aggressive and with poor prognosis. The mechanisms that drive cholangiocyte transition towards malignant phenotype are obscure. Cholangiocyte benign proliferation is subjected to a self-limiting mechanism based on the autocrine release of endogenous opioid peptides. Despite the presence of both, ligands interact with delta opioid receptor (OR), but not with microOR, with the consequent inhibition of cell growth. We aimed to verify whether cholangiocarcinoma growth is associated with failure of opioidergic regulation of growth control.
  
  
  METHODS
  We evaluated the effects of OR selective agonists on cholangiocarcinoma cell proliferation, migration and apoptosis. Intracellular signals were also characterised.
  
  
  RESULTS
  Activation of microOR, but not deltaOR, increases cholangiocarcinoma cell growth. Such an effect is mediated by ERK1/2, PI3K and Ca(2+)-CamKIIalpha cascades, but not by cAMP/PKA and PKCalpha. microOR activation also enhances cholangiocarcinoma cell migration and reduces death by apoptosis. The anti-apoptotic effect of microOR was PI3K dependent.
  
  
  CONCLUSIONS
  Our data indicate that cholangiocarcinoma growth is associated with altered opioidergic regulation of cholangiocyte biology, thus opening new scenarios for future surveillance or early diagnostic strategies for cholangiocarcinoma.
authors.affiliation: Department of Gastroenterology, Politechnic University of Marche, Ancona, Italy. m.marzioni@univpm.it
authors.forename: M
authors.initials: M
authors.lastname: Marzioni
authors.forename: P
authors.initials: P
authors.lastname: Invernizzi
authors.forename: C
authors.initials: C
authors.lastname: Candelaresi
authors.forename: M
authors.initials: M
authors.lastname: Maggioni
authors.forename: S
authors.initials: S
authors.lastname: Saccomanno
authors.forename: C
authors.initials: C
authors.lastname: Selmi
authors.forename: C
authors.initials: C
authors.lastname: Rychlicki
authors.forename: L
authors.initials: L
authors.lastname: Agostinelli
authors.forename: B
authors.initials: B
authors.lastname: Cassani
authors.forename: M
authors.initials: M
authors.lastname: Miozzo
authors.forename: S
authors.initials: S
authors.lastname: Pasini
authors.forename: G
authors.initials: G
authors.lastname: Fava
authors.forename: G
authors.initials: G
authors.lastname: Alpini
authors.forename: A
authors.initials: A
authors.lastname: Benedetti
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu